Allelic differences between Europeans and Chinese for CREB1 SNPs and their implications in gene expression regulation, hippocampal structure and function, and bipolar disorder susceptibility

• Published in: Molecular psychiatry Vol. 19; no. 4; pp. 452 - 461
• Main Authors: Li, M, Luo, X-j, Rietschel, M, Lewis, C M, Mattheisen, M, Müller-Myhsok, B, Jamain, S, Leboyer, M, Landén, M, Thompson, P M, Cichon, S, Nöthen, M M, Schulze, T G, Sullivan, P F, Bergen, S E, Donohoe, G, Morris, D W, Hargreaves, A, Gill, M, Corvin, A, Hultman, C, Toga, A W, Shi, L, Lin, Q, Shi, H, Gan, L, Meyer-Lindenberg, A, Czamara, D, Henry, C, Etain, B, Bis, J C, Ikram, M A, Fornage, M, Debette, S, Launer, L J, Seshadri, S, Erk, S, Walter, H, Heinz, A, Bellivier, F, Stein, J L, Medland, S E, Arias Vasquez, A, Hibar, D P, Franke, B, Martin, N G, Wright, M J, Su, B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2014; Nature Publishing Group
• Subjects: 631/208/205; 631/208/457/649; 692/699/476/1333; Adult; Adult and adolescent clinical studies; Age Factors; Aged; Aged, 80 and over; Alleles; Alzheimer's disease; Asian Continental Ancestry Group - genetics; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Bipolar disorder; Bipolar Disorder - ethnology; Bipolar Disorder - genetics; Bipolar disorders; Brain research; Case-Control Studies; Cognitive ability; Computational Biology; Consortia; Cyclic AMP Response Element-Binding Protein - genetics; Epidemiology; European Continental Ancestry Group - genetics; Female; Gene expression; Gene Expression Regulation - genetics; Gene frequency; Gene Frequency - genetics; Gene regulation; Genetic analysis; Genetic aspects; Genetic Association Studies; Genetic markers; Genetic Predisposition to Disease; Genetic research; Genetic susceptibility; Genetics; Health care; Health risk assessment; Hippocampus; Hippocampus - pathology; Hospitals; Humans; Identification and classification; Laboratories; Life Sciences; Male; Medical imaging; Medical research; Medical sciences; Medicine; Medicine & Public Health; Mental depression; Mental health; Middle Aged; Miscellaneous; Mood disorders; Natural selection; Neuroimaging; Neurology; Neuropsychological Tests; Neurosciences; original-article; Pharmacotherapy; Phenotype; Phenotypes; Polymorphism, Single Nucleotide - genetics; Population genetics; Prefrontal cortex; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychotherapy; Risk factors; RNA, Messenger - metabolism; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Structure-function relationships; Susceptibility; Zoology; Los Angeles California; Sweden; Netherlands; Queensland Australia; United States > US; Berlin Germany; China; Paris France; California; Australia; France; Germany; intermediate phenotype; association; bipolar disorder; natural selection; gene expression; Mood disorder; Central nervous system; Bipolar disorder; Gene expression; Genetic determinism; Encephalon; Natural selection; Phenotype; Sensitivity; CREB1; Genetics; Chinese; Comparative study; Hippocampus
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2013.37

Bipolar disorder (BD) is a polygenic disorder that shares substantial genetic risk factors with major depressive disorder (MDD). Genetic analyses have reported numerous BD susceptibility genes, while some variants, such as single-nucleotide polymorphisms (SNPs) in CACNA1C have been successfully replicated, many others have not and subsequently their effects on the intermediate phenotypes cannot be verified. Here, we studied the MDD-related gene CREB1 in a set of independent BD sample groups of European ancestry (a total of 64 888 subjects) and identified multiple SNPs significantly associated with BD (the most significant being SNP rs6785[A], P =6.32 × 10 −5 , odds ratio (OR)=1.090). Risk SNPs were then subjected to further analyses in healthy Europeans for intermediate phenotypes of BD, including hippocampal volume, hippocampal function and cognitive performance. Our results showed that the risk SNPs were significantly associated with hippocampal volume and hippocampal function, with the risk alleles showing a decreased hippocampal volume and diminished activation of the left hippocampus, adding further evidence for their involvement in BD susceptibility. We also found the risk SNPs were strongly associated with CREB1 expression in lymphoblastoid cells ( P <0.005) and the prefrontal cortex ( P <1.0 × 10 −6 ). Remarkably, population genetic analysis indicated that CREB1 displayed striking differences in allele frequencies between continental populations, and the risk alleles were completely absent in East Asian populations. We demonstrated that the regional prevalence of the CREB1 risk alleles in Europeans is likely caused by genetic hitchhiking due to natural selection acting on a nearby gene. Our results suggest that differential population histories due to natural selection on regional populations may lead to genetic heterogeneity of susceptibility to complex diseases, such as BD, and explain inconsistencies in detecting the genetic markers of these diseases among different ethnic populations.